Basal cell carcinoma is a common, non-melanoma skin cancer, originating in the basal stem cells of the epidermis. The sun-exposed areas of the head and neck are the most commonly involved sites. Basal cell carcinoma (BCC) predominantly affects Caucasians and is very uncommon in dark-skinned races. BCC is the most common cancer in Europe, Australia and the USA and is showing a worldwide increase in incidence. The most significant aetiological factors appear to be genetic predisposition and exposure to ultraviolet (UV) radiation.
At the moment surgery and radiotherapy appear to be the most effective treatments for BCC, with surgery showing the lowest failure rates. There is only limited evidence of the effectiveness of other treatment modalities compared with surgery, e.g. topical chemotherapy (Imiquimod and Fluoroacil 5% creams). The present inventors therefore sought alternative and/or combinatorial treatments for this condition.
It has been observed that treatment with non-steroid anti-inflammatory drugs (NSAIDS) that target the arachidonyl cascade may reduce cancer progression (Johannesdottir, S. A., et al., Nonsteroidal anti-inflammatory drugs and the risk of skin cancer: a population-based case-control study. Cancer, 2012. 118(19): p. 4768-76; Gonzalez-Periz, A. and J. Claria, New approaches to the modulation of the cyclooxygenase-2 and 5-lipoxygenase pathways. Curr Top Med Chem, 2007. 7(3): p. 297-309).
The present inventors postulate that cytosolic phospholipase A2 group IVa (cPLA2α) enzyme may be involved in the pathogenesis of basal cell carcinoma and other related cancers.
The phospholipases A2 enzymes are a group of lipases that by hydrolysis release unsaturated fatty acids from the sn2 position of membrane phospholipids. Once released, the fatty acids are converted by various enzymes into biologically important signalling molecules. Cytosolic group IVa PLA2 (cPLA2α) is pivotal in inflammation; it is activated by intracellular calcium and by phosphorylation in response to stimuli such as pro-inflammatory cytokines and mitogenic growth factors. cPLA2α is selective for AA-containing acyl chains in vitro, and is considered a central enzyme in AA-derived eicosanoid production. Release of arachidonate initiates the arachidonate cascade leading to the synthesis of eicosanoids such as prostaglandins. Eicosanoids are important in a variety of physiological processes and play a central role in inflammation. Elevated levels of arachidonic acid, eicosanoids and other bioactive lipid mediators are reported in inflammatory dermatoses.
The present inventors also realise that a chronic inflammatory microenvironment is now recognized as a hallmark of cancer, promoting the progression of malignancy, including initiation, growth, angiogenesis, invasion and metastasis.
Of the pro-inflammatory mediators, lipid autocoids such as platelet activating factor, lysophosphatidic acid, prostaglandins and leukotrienes, with their specific receptors and pathways, have been shown to play a critical role in cancer initiation and progression. Hence, bioactive lipids may represent a link between inflammation and cancer.
It is therefore possible that inhibition of the cPLA2α enzyme, the limiting factor for arachidonic acid and lysophopholipid release and availability, should have potential in reducing the inflammatory events promoting aberrant, cancerous basal cell activity due to reduced production of bioactive lipids such as LTB4 and PGE2, in basal cell carcinoma and other related cancers.
Holmeide and Skattebøl reported in 2000 that several structurally different compounds are reported as inhibitors of cPLA2α in vitro (Journal of the chemical society-Perkin transactions, 2000. 1(14): p. 2271-2276). The compounds tested were based around (all-Z)-eicosa-5,8,11,14-,17-pentaenoic acid (EPA) and (all-Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA).
In recent publications we validated the Perkins Transactions paper finding of in vitro target efficacy and furthermore show potent cellular anti-inflammatory effects in both mesangial and synovial cells (Huwiler, A., et al., British Journal of Pharmacology, 2012. 167(8): p. 1691-1701; Sommerfelt, R. M., et al., Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes. PLoS ONE, 2013. 8(12): p. e83555).
The treatment of cancer however is complex and the person skilled in the art appreciates that to target cancer successfully requires more than just cPLA2 inhibition.
The pleiotropic epidermal growth factor (EGF) and its receptors (EGFR, HER2, HER3, HER4) are recognized to have pivotal roles in various solid tumours and the EGF pathway is commonly targeted in cancer treatment. In the epidermis, EGFR is predominantly expressed in the basal layer, with increased expression in basal-cell carcinoma relative to normal skin. Furthermore, the phenomenon of EGFR receptor transactivation by bioactive lipids binding to their G-protein coupled receptors (GPCRs) adds to the complexity of EGFR dependent carcinogenic events.
An association between cPLA2α, the arachidonate cascade and EGF/EGFRs is described in several model systems and types of cancer; e.g. human cervical carcinoma HeLa cells, in lung epithelial cells, in the kidney and in squamous cell carcinoma keratinocytes (Matsuzawa, Y., et al., J Pharmacol Sci, 2009. 111(2): p. 182-92; Liu, M., et al., American Journal of Respiratory Cell and Molecular Biology, 2007. 37(5): p. 578-88; Alexander, L. D., et al., Kidney International, 2006. 69(10): p. 1823-32; Johnson, F. M., et al., Journal of Experimental Therapeutics and Oncology, 2004. 4(4): p. 317-25).
As outlined, EGFR and COX/LOX are accepted treatment targets in cancer, including BCC. However, there are no reports on the effects of targeting the common interactor enzyme cPLA2α in an effort to modulate and normalize these aberrant signalling events in cancer. The biochemistry here is therefore complex and unpredictable.
The present inventors have surprisingly found that:
1) EGF activates cPLA2α in keratinocytes in a time-dependent manner;
2) EGF-induced cPLA2α activity is halted by use of certain polyunsaturated ketones in a dose-dependent manner;
3) Use of polyunsaturated ketones such as AVX001 defined herein reduce EGF-meditated keratinocyte proliferation, indicating the rationale to target cPLA2α in BCC and other related cancers.
The compounds proposed for use in this invention have been disclosed before, for example, in EP-A-1469859 but only in the treatment of psoriasis which is a skin condition but is not a form of skin cancer. Psoriasis is an autoimmune induced, chronic disease of skin, characterized by T-cell accumulation, inflammation and hyperproliferation of keratinocytes in epidermis.
Psoriasis has very different biochemistry/immunology than BCC. The compounds have also been suggested, in WO2010/139482, for the treatment of glomerulonephritis or for the treatment of rheumatoid arthritis in WO2012/028688. Again, these uses are far removed from the present application.
The present inventors have now shown experimentally that the compounds of the invention have utility in the treatment of skin cancer through a series of valuable biochemical processes, not limited to cPLA2 inhibition. It is the ability of these compounds to affect multiple biochemical processes that makes them attractive in skin cancer treatment.